POTENTIAL FOR IMPROVED THERAPEUTIC INDEX OF FK506 IN LIPOSOMAL FORMULATION DEMONSTRATED IN A MOUSE CARDIAC ALLOGRAFT MODEL1,2:

Background. FK506 is a potent immunosuppressant that has improved clinical outcomes in kidney and liver transplantation both as a primary and as a rescue immunosuppressive agent. Despite these benefits, the potential value of FK506 is limited by toxic side effects that result in a narrow therapeutic index, By encapsulating the active drug within liposomes (LipoFK506), a new formulation has been developed that might improve this therapeutic index. Methods. The biodistribution of tritiated-FK506 administered i.v. showed that the drug remained associated with the liposomal carrier in vivo, and that its tissue distribution was increased in heart and spleen compared to nonliposomal FK506, The immunosuppressive efficacy of lipoFK506 compared with conventional FK506 formulation was tested in vivo. CBA (H2(k)) mice were engrafted with BALB/c (H2(d)) mouse hearts with daily immunosuppression using either 1 mg/kg FK506, or 1 mg/kg LipoFK506, from day 0 to 14. Results. At day 7 the blood trough level of FK506 in the FK506 group was 10-fold higher (25 mu g/L) than that in the LipoFK506 group, In both groups the median heart allograft survival was similar at around 26 days. The possibility that FK506, or LipoFK506, might influence antibody-mediated tolerogenesis was addressed in the same model: neither formulation prevented tolerance induction by CD4 and CD8 blockade. Conclusion. LipoFK506 is a novel formulation of FK506 that is efficacious at low blood trough FR506 levels. This property has a direct potential benefit for clinical organ transplantation.